One-pot synthesis of chiral multifunctionalized aziridines

Article abstract of DOI:10.1016/j.tet.2008.11.017

A direct synthetic procedure to obtain chiral aziridines is reported, involving a diastereoselective aza-MIRC (Michael Initiated Ring Closure) reaction. Multifunctionalized aziridines are obtained in high overall yields (82-92%) and with a diastereomeric

Full text of DOI:10.1016/j.tet.2008.11.017

Tetrahedron 65 (2009) 484–488
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
One-pot synthesis of chiral multifunctionalized aziridines
*
*
*
Stefania Fioravanti , Sara Morea, Alberto Morreale, Lucio Pellacani , Paolo A. Tardella
`
Dipartimento di Chimica, Universita degli Studi ‘La Sapienza’, P.le Aldo Moro 2, I-00185 Roma, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
A direct synthetic procedure to obtain chiral aziridines is reported, involving a diastereoselective aza-
MIRC (Michael Initiated Ring Closure) reaction. Multifunctionalized aziridines are obtained in high
overall yields (82–92%) and with a diastereomeric ratio up to 99:1. Further synthetic elaboration can lead
to the formation of interesting biochemical molecules, such as amino glycosides. The diastereomeric
induction seems to be strongly controlled both by the choice of chiral moiety and by the electron
withdrawing groups (EWG) present on the starting alkenes.
Received 1 September 2008
Received in revised form 24 October 2008
Accepted 6 November 2008
Available online 12 November 2008
Keywords:
Michael addition
Amination
Ó 2008 Elsevier Ltd. All rights reserved.
Asymmetric induction
Heterocycles
1. Introduction
Continuing our studies on the stereoselective aza-MIRC re-
actions, here we report the two step one-pot synthesis of highly
The development of procedures leading to the stereocontrolled
formation of carbon–nitrogen bonds is considered a challenging
research topic. The aza-Michael reaction is a very simple tool to
synthesize chiral nitrogen-containing compounds, owing to its
simplicity and usefulness. The most successful strategies to achieve
asymmetric induction include the use of a chiral amine or Michael
acceptor or catalyst.1 The aza-MIRC (Michael Initiated Ring Closure)
reaction represents an intriguing approach to obtain in one syn-
thetic step the formation of small or medium sized nitrogen-con-
taining ring systems. However, this approach has not been
investigated fully.
functionalized chiral aziridines, starting from cyano methylene
compounds and (R)-2,2-dimethyl-1,3-dioxolane-4-carboxaldehyde4
(1) or Garner’s aldehyde5 (2) (Scheme 1).
EWG
CN
CN
EWG
NsONHCO2Et
+
N
CO2Et
R*CHO
R*
O
O
O
N
Boc
During the last years, we found that N-protected O-sulfonyl
hydroxylamine derivatives in the presence of inorganic bases give
a highly regio- and stereoselective aza-Michael initiated aziridi-
nation reaction on functionalized alkenes.2
R*-CHO =
CHO
CHO
1
2
Scheme 1. Two step one-pot synthesis of chiral cyano functionalized aziridines.
This reaction has been applied with success also to the chiral
synthesis of different substituted aziridines either by using chiral
auxiliaries on the alkenes or on the aminating agents but also by
using chiral catalysts.
2. Results and discussion
Recently, we reported the synthesis of diastereomerically pure
nitro aziridines by a stereoselective aza-MIRC reaction performed
on optically active (E)-nitro alkenes carrying a 1,3-dioxolane or 1,3-
oxazolidine residue, useful precursors of important chemical
functionality.3
For the synthesis of the intermediate chiral cyano acrylates 6
and 7 and oxo acrylonitriles 8–11, classical condensation reaction
conditions (piperidine/toluene, reflux) failed because of uncon-
trolled decomposition and/or polymerization reactions favored by
the high temperatures. Consequently, an Al2O3 induced Knoeve-
nagel reaction was attempted.6 Under these conditions the target
products were obtained in unsatisfactory yields (<30%).
Finally, a synthetic strategy involving the use of catalytic pi-
peridine in an equimolar CH2Cl2 solution of reactants at room
temperature was successfully performed (Scheme 2) and the
* Corresponding authors. Tel.: þ39 0649913673; fax: þ39 06490631.
E-mail address: lucio.pellacani@uniroma1.it (L. Pellacani).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.11.017

S. Fioravanti et al. / Tetrahedron 65 (2009) 484–488
485
Table 2
EWG
CN
R*
1 or 2, piperidine
CH2Cl2, rt, 15'
Results of aziridination reactions
CN
EWG
Entry
Aziridine
R*CHO
EWG
Time (h)
Yielda (%)
drb
3-5
R*-CHO =
6-11
1
2
3
4
5
6
12/120
13/130
14/140
15
1
2
1
2
1
2
CO2Et
CO2Et
COPh
COPh
COt-Bu
COt-Bu
1
4
1
2
4
4
82
85
90
87
92
83
8:2
7:3
8:2
>99:1
6:4
Boc
N
O
O
O
CHO
CHO
2
16/160
17
1
>99:1
Scheme 2. Mild conditions to synthesize chiral cyano alkenes.
a
After purification, calculated on the starting aldehydes.
Determined by HPLC–UV.
b
Table 1
Synthesis of (E)-chiral alkenes
on the stereoselective induction were observed when the EWG was
an acyl group (entries 3–6).
Substrate
EWG
R*CHO
Alkene
Yielda (%)
Starting from 4 and 5, the stereochemical aziridination outcome
was found to be strongly influenced by the choice of the chiral al-
dehyde. In fact, using the chiral aldehyde 1 (entries 3 and 5)
a moderate stereoselective induction was observed, especially in
the presence of the tert-butyl group. In contrast, a very high di-
astereomeric purity was obtained using Garner’s aldehyde 2 re-
gardless of the group on the carbonyl function (entries 4 and 6).
The cyano acyl aziridines 14–17 were found to be stable com-
pounds, rearranging slowly into the isomeric 2,3-dihydrooxazoles,
in contrast to the behavior previously reported for analogous
heterocycles.9 1H NMR spectra performed on a sample of azir-
idines 16 and 160 stored at room temperature in CDCl3 for two
3
CO2Et
1
2
1
2
1
2
6
7
8
9
10
11
76
65
72
80
68
75
4
5
COPh
COt-Bu
a
After fast filtration of reaction mixtures on short plugs filled with silica gel using
200 mL of a hexane/ethyl acetate 8:2 mixture.
desired alkenes were obtained after 15 min stirring in very high
yields and purities (Table 1).
Chiral alkenes were obtained as pure E isomers7 in high purity as
showed by 1H NMR spectra and HPLC–UV analyses performed on
the crude filtrates. Longer reaction times give rise to lower product
yields.
months showed the presence of two doublets at
d 5.95 attribut-
able to the isomeric 2,3-dihydrooxazoles. As determined by in-
tegration analyses, the initial dr of the corresponding aziridines
was maintained.
The absolute configuration of the new chiral centers of the
major aziridine diastereomers was tentatively assigned according
to the data reported for the same diastereoselective aza-MIRC re-
action performed on chiral nitro alkenes. The major diastereomer
obtained by using 1 as the chiral residue can be explained by the
coordination of the nucleophilic reagent by the dioxolane oxygen,10
while the absolute configuration of the major aziridine di-
astereomers 13, 15, and 17 was assigned according to the results of
X-ray analysis we performed on a similar chiral substrate.3
Finally, our attention turned toward chemoselective ring
opening reactions of the 1,3-dioxolane and the 1,3-oxazolidine ring,
leading to chiral multifunctionalized aziridines, useful scaffolds in
the construction of interesting structures, like amino glycosides.
Starting from 12, the dioxolane ring was hydrolyzed at room
temperature with HCl to form the diol derivative 19, in quantitative
yield after 30 min11 (Scheme 4).
The optimal reaction conditions to obtain alkenes 6–11 sug-
gested a two step one-pot aziridination reaction starting directly
from methylene active compounds and chiral aldehydes.
Therefore, catalytic piperidine (5 mol %) was added at room
temperature to an equimolar solution of methylene active com-
pounds 3–5 and optically active aldehydes in CH2Cl2. After 15 min,
a two-fold excess of CaO and a four-fold excess of NsONHCO2Et
were added at room temperature (Scheme 3).
The aziridination step was monitored by TLC analysis and the
results are reported in Table 2.
As reported in Table 2, in all cases the aziridines were obtained
in high overall yields and in moderate to high diastereo-
selectivities (up to 99:1 dr) with retention of the starting alkene
configurations, according to the previous results we reported for
the synthesis of N-protected cyano aziridines by the same aza-
MIRC reaction on several (E)-2-cyano acrylates.8 Flash chroma-
tography on silica gel (eluent: hexane/ethyl acetate 80:20) allowed
to obtain the aziridines (entries 1–3 and 5) directly as pure
diastereomers.
The deprotection reaction of the acetonide function of 13 was
attempted in the presence of Montmorillonite K10 clay (20% w/
w),12 but the starting material was quantitatively recovered after
48 h. The desired hydrolysis took place using HCl in THF at reflux for
Using a carboxylic group as EWG comparable results were
obtained in the yields and in the drs even by changing the chiral
moiety (entries 1 and 2). On the other hand, interesting differences
1.5 h, giving
b-amino alcohol 20 as main product. The presence of
aziridine 13 and of diethyl (2R,3R)-2-cyano-3-[(4S)-2,2-dimethyl-
EWG
CN
CN
N
CN
N
EWG
EWG
i) 1 or 2, piperidine, CH2Cl2, rt, 15'
ii) NsONHCO2Et, CaO, 1-4 h
+
+
CO2Et
CO2Et
R*CHO
R*
R*
12-17
12'-14', 16'
Boc
N
O
O
O
EWG = CO2Et; COPh, COt-Bu
R*-CHO =
CHO
CHO
2
1
Scheme 3. Direct synthesis of chiral functionalized cyano aziridines.

486
S. Fioravanti et al. / Tetrahedron 65 (2009) 484–488
O
4.2. Synthesis of chiral (E)-cyano alkenes 6–11. General
procedure
O
CN
CN
EtO
EtO
EtO
2M HCl,THF
rt, 30'
N CO2Et
O
N
CO2Et
To a solution of cyano methylene compounds 3–5 (3 mmol) in
CH2Cl2 (3.0 mL), chiral aldehyde 1 or 2 (3 mmol) and catalytic pi-
peridine (0.15 mmol) were added. The reaction mixture was stirred
for 15 min at room temperature (TLC) and purified by flash chro-
matography (hexane/ethyl acetate 8:2).
HO
19
O
OH
12
O
O
CN
EtO
CN
N
CO2Et
4.2.1. Ethyl (2E)-2-cyano-3-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]
prop-2-enoate 6
2M HCl, THF
reflux, 1.5 h
N
CO2Et
O
H2N
Yellow oil (0.52 g, 76%). [
1634 cmꢁ1. 1H NMR (300 MHz, CDCl3)
5.8 Hz, 1H), 3.80 (d, J 5.8 Hz, 1H), 4.20–4.42 (m, 2H), 4.86–5.24 (m,
1H), 7.55 (d, J 8.0 Hz,1H).13C NMR (75 MHz, CDCl3)
: 13.9, 25.3, 26.3,
a]
D þ12.3 (c 1.0, CHCl3). IR: 2234, 1733,
OH
Boc
13
N
d
: 1.20–1.41 (m, 9H), 3.76 (d, J
20
Scheme 4. Chemoselective ring opening reactions of the 1,3-dioxolane and the 1,3-
oxazolidine ring.
d
62.8, 68.2, 73.6, 93.3,110.3,112.6,135.8,160.3. HRMS(ESQ-TOF)calcd
for C11H15NNaO4 (MþNa)þ: 248.0899; found: 248.0907.
1,3-oxazolidin-4-yl]aziridine-1,2-dicarboxylate (21) were detected
by ESI-MS spectra performed on the crude mixture.
4.2.2. tert-Butyl (4S)-4-[(1E)-2-cyano-3-ethoxy-3-oxoprop-1-en-
1-yl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate 7
O
CN
Yellow oil (0.62 g, 65%). [
1632 cmꢁ1. 1H NMR (300 MHz, CDCl3)
J 5.8 Hz, 1H), 3.79 (d, J 5.8 Hz, 1H), 4.16–4.32 (m, 2H), 4.80 (m, 1H),
7.43 (d, J 10.2 Hz, 1H). 13C NMR (75 MHz, CDCl3)
: 13.9, 25.8, 26.2,
a]
þ8.8 (c 1.0, CHCl3). IR: 2235, 1731,
EtO
D
N
d
: 1.08–1.84 (m, 18H), 3,74 (d,
CO2Et
HN
O
d
28.2, 62.7, 66.7, 72.1, 81.2, 94.5, 110.0, 112.7, 137.9, 156.3, 160.6.
HRMS (ES Q-TOF) calcd for C16H24N2NaO5 (MþNa)þ: 347.1583;
found: 347.1580.
21
Longer reaction times led to a complex reaction mixture, due to
uncontrolled opening reactions of aziridine ring. Interestingly in
both cases the aziridine ring was unaffected.
4.2.3. (2E)-3-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-2-
(phenylcarbonyl)prop-2-enenitrile 8
Yellow oil (0.54 g, 72%). [
1705, 1610 cmꢁ1 1H NMR (300 MHz, CDCl3)
6H), 3.38–3.82 (m, 2H), 4.83–5.10 (m, 1H), 7.43–7.85 (m, 6H).
13C NMR (75 MHz, CDCl3)
: 26.4 (2C), 69.5, 74.2, 95.1, 111.8,
a
]
þ16.4 (c 1.0, CHCl3). IR: 2204,
D
.
d: 1.02–1.68 (m,
3. Conclusions
d
In summary, a direct synthetic procedure to obtain aziridines
was reported, involving a diastereoselective aza-MIRC reaction. The
functional groups and the chiral moieties present on the aziridine
ring allow further chemical transformation addressed to multi-step
syntheses of different biomolecular targets, by ring opening re-
actions and focused elaborations of the carbonyl13 and the cyano
functions.14
115.0, 128.0, 129.6, 134.6, 136.7, 152.8, 182.3. HRMS (ES Q-
TOF) calcd for C15H15NNaO3 (MþNa)þ: 280.0950; found:
280.0943.
4.2.4. tert-Butyl (4S)-4-[(1E)-2-cyano-3-oxo-3-phenylprop-1-en-
1-yl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate 9
Yellow oil (0.85 g, 80%). [
1598 cmꢁ1. 1H NMR (300 MHz, CDCl3)
3.80 (m, 2H), 4.93–5.18 (m, 1H), 7.23 (d, J 9.5 Hz, 1H), 7.13–7.55 (m,
5H). 13C NMR (75 MHz, CDCl3)
: 23.3 (2C), 27.1, 67.6, 73.4, 81.2,
a]
D þ18.3 (c 1.0, CHCl3). IR: 2169, 1698,
d
: 0.96–1.72 (m, 15H), 3.35–
4. Experimental section
4.1. General
d
92.4, 113.8, 117.0, 127.5, 128.0, 132.9, 136.2, 154.7, 156.3, 197.3. HRMS
(ES Q-TOF) calcd for C20H24N2NaO4 (MþNa)þ: 379.1634; found:
379.1643.
GC–MS analyses were performed with a HP G1800A gas chro-
matograph equipped with a capillary column (phenyl methyl sili-
cone, 30 mꢀ0.25 mm). IR spectra were recorded on a PERKIN
ELMER 1600 FT/IR spectrophotometer in CHCl3 as the solvent, and
reported in cmꢁ1. 1H NMR and 13C NMR spectra were recorded at
300 and 75 MHz or at 200 and 50 MHz with a Varian XL-300 or
Gemini 200 NMR spectrometer, respectively, and reported in
4.2.5. (2E)-2-{[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]methylidene}-
4,4-dimethyl-3-oxopentanenitrile 10
Yellow oil (0,48 g, 68%). [
1702 cmꢁ1. 1H NMR (300 MHz, CDCl3)
3.79 (m, 2H), 4.92–5.16 (m, 1H), 7.48 (d, J 8.0 Hz, 1H). 13C NMR
a
]
þ11.0 (c 1.0, CHCl3). IR: 2200,
D
d
: 0.97–1.74 (m, 15H), 3.36–
d
units. CDCl3 was used as the solvent and CHCl3 as the internal
(75 MHz, CDCl3) d: 26.1 (2C), 28.5, 69.7, 75.8, 79.6, 94.6, 110.1, 115.2,
standard. ESI-MS analyses were performed using a Micromass
Q-TOF Micro quadrupole-time of flight (TOF) mass spectrometer
equipped with an ESI source and a syringe pump. The experiments
were conducted in the positive ion mode. Optical rotations were
determined with a JASCO DIP-370 polarimeter at 20 ꢂC. HPLC
analyses were performed with a VARIAN 9002 instrument using an
analytical column (3.9ꢀ300 mm, flow rate 1.3 mL/min; detector:
254 nm) equipped with a VARIAN 9040 differential refractometer,
or a VARIAN 9050 UV/VIS detector. Eluents were HPLC grade. An-
alytical thin-layer chromatography (TLC) was carried out on pre-
coated silica gel plates. Silica gel 230–400 mesh was used for
column chromatography.
154.5, 193.2. HRMS (ES Q-TOF) calcd for C13H19NNaO3 (MþNa)þ:
260.1263; found: 260.1270.
4.2.6. tert-Butyl (4S)-4-[(1E)-2-cyano-4,4-dimethyl-3-oxopent-1-
en-1-yl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate 11
Yellow oil (0.76 g, 75%). [
1711 cmꢁ1 1H NMR (300 MHz, CDCl3)
3.56–3.93 (m, 2H), 4.63–5.01 (m, 1H), 7.42 (d, J 9.5 Hz, 1H).
13C NMR (75 MHz, CDCl3)
: 25.4, 26.2, 28.3, 29.5, 67.1, 73.2,
a
]
þ6.2 (c 1.0, CHCl3). IR: 2169,
D
.
d: 0.96–1.86 (m, 24H),
d
79.8, 81.1, 99.3, 115.4, 116.8, 135.0, 157.2, 192.6. HRMS (ES
Q-TOF) calcd for C18H28N2NaO4 (MþNa)þ: 359.1947; found:
359.1940.

S. Fioravanti et al. / Tetrahedron 65 (2009) 484–488
487
4.3. One-pot synthesis of chiral functionalized aziridines.
General procedure
3.12 (d, J 5.6 Hz, 1H), 4.03–4.44 (m, 5H), 7.32–7.78 (m, 5H). 13C
NMR (50 MHz, CDCl3) : 14.2, 25.6, 26.1, 52.8, 57.6, 64.4, 68.2, 72.5,
d
98.0, 113.2, 128.1, 128.9, 129.5, 134.4, 156.1, 201.0. HRMS (ES
Q-TOF) calcd for C18H20N2NaO5 (MþNa)þ: 367.1270; found:
367.1268.
To a stirred solution of cyano methylene compounds 3–5
(3 mmol) in CH2Cl2 (3.0 mL), chiral aldehyde 1 or 2 (3 mmol) and
a catalytic amount of piperidine (0.15 mmol), after 15 min a two-
fold excess of CaO and a four-fold excess of NsONHCO2Et were
added at room temperature. After the time reported in Table 2, the
crude mixtures were purified by flash chromatography (hexane/
ethyl acetate 8:2), giving directly the optically pure diastereomeric
aziridines.
4.3.7. tert-Butyl (4S)-4-[(2R,3R)-3-cyano-1-(ethoxycarbonyl)-3-
(phenylcarbonyl)aziridin-2-yl]-2,2-dimethyl-1,3-oxazolidine-3-
carboxylate 15
Pale yellow oil (1.16 g, 87%). [
1738, 1694, 1598 cmꢁ1. 1H NMR (300 MHz, CDCl3)
18H), 3.05 (d, J 7.3 Hz, 1H), 4.00–4.32 (m, 5H), 7.60–8.00 (m, 5H). 13C
NMR (75 MHz, CDCl3) : 13.0, 26.2 (2C), 27.4, 38.3, 58.2, 63.7, 64.6,
a
]
þ19.0 (c 1.0, CHCl3). IR: 2217,
D
d
: 1.00–1.79 (m,
4.3.1. Diethyl (2R,3S)-2-cyano-3-[(4S)-2,2-dimethyl-1,3-dioxolan-
d
4-yl]aziridine-1,2-dicarboxylate 12
65.1, 79.7, 93.7, 114.3, 127.2, 127.7, 128.3, 133.5, 156.9, 159.0, 198.2.
HRMS (ES Q-TOF) calcd for C23H29N3NaO6 (MþNa)þ: 466.1954;
found: 466.1966.
Pale yellow oil (0.62 g, 66%). [
1757, 1735 cmꢁ1 1H NMR (300 MHz, CDCl3)
1.47 (s, 6H), 3.24 (d, J 8.1 Hz, 1H), 3.86–4.09 (m, 2H), 4.11–4.26 (m,
4H), 4.30–4.44 (m, 1H). 13C NMR (75 MHz, CDCl3)
: 13.8, 14.0, 24.8,
a
]
þ2.2 (c 1.0, CHCl3). IR: 2256,
D
.
d: 1.15–1.51 (m, 6H),
d
4.3.8. Ethyl (2R,3S)-2-cyano-3-[(4S)-2,2-dimethyl-1,3-dioxolan-4-
26.5, 37.9, 50.7, 63.9, 64.1, 67.5, 74.2, 86.1, 111.2, 156.6, 162.3. HRMS
(ES Q-TOF) calcd for C14H20N2NaO6 (MþNa)þ: 335.1219; found:
335.1225.
yl]-2-(2,2-dimethylpropanoyl)aziridine-1-carboxylate 16
Pale yellow oil (0.53 g, 55%). [
1744, 1716 cmꢁ1. 1H NMR (200 MHz, CDCl3)
1.36 (s, 3H), 1.37 (s, 3H), 3.07 (d, J 7.3 Hz, 1H), 3.43–4.06 (m, 2H),
4.12–4.36 (m, 2H), 4.43–4.64 (m, 1H). 13C NMR (50 MHz, CDCl3)
a]
þ8.2 (c 1.0, CHCl3). IR: 2201,
D
d
: 1.03–1.79 (m, 12H),
4.3.2. Diethyl (2S,3R)-2-cyano-3-[(4S)-2,2-dimethyl-1,3-dioxolan-
4-yl]aziridine-1,2-dicarboxylate 120
d:
14.1, 25.4, 26.5, 28.0, 39.4, 57.1, 63.4, 66.2, 74.4, 80.3, 96.3, 110.8,
157.5, 199.3. HRMS (ES Q-TOF) calcd for C16H24N2NaO5 (MþNa)þ:
347.1583; found: 347.1581.
Pale yellow oil (0.15 g, 16%). [
a]
þ3.9 (c 1.0, CHCl3). IR: 2256,
D
1757, 1735 cmꢁ1 1H NMR (300 MHz, CDCl3)
.
d: 1.02–1.62 (m, 6H),
1.45 (s, 6H), 3.23 (d, J 6.7 Hz, 1H), 3.94 (d, J 3.6 Hz, 1H), 3.98 (d, J
3.6 Hz,1H), 4.03–4.15 (m, 4H), 4.22–4.59 (m,1H). 13C NMR (75 MHz,
4.3.9. Ethyl (2S,3R)-2-cyano-3-[(4S)-2,2-dimethyl-1,3-dioxolan-4-
yl]-2-(2,2-dimethylpropanoyl)aziridine-1-carboxylate 160
CDCl3)
d: 13.8, 14.0, 25.1, 26.5, 36.2, 50.4, 63.8, 64.5, 66.6, 74.2, 87.2,
111.3, 157.2, 162.4. HRMS (ES Q-TOF) calcd for C14H20N2NaO6
Pale yellow oil (0.36 g, 37%). [
1744, 1716 cmꢁ1. 1H NMR (200 MHz, CDCl3)
1.36 (s, 3H), 1.37 (s, 3H), 3.02 (d, J 8.0 Hz, 1H), 3.76–4.34 (m, 4H),
4.40–4.63 (m, 1H). 13C NMR (50 MHz, CDCl3)
: 13.9, 24.6 (2C), 28.4,
a
]
þ12.0 (c 1.0, CHCl3). IR: 2201,
D
(MþNa)þ: 335.1219; found: 335.1228.
d: 0.99–1.86 (m, 12H),
4.3.3. Diethyl (2R,3R)-2-cyano-3-[(4S)-3-(tert-butoxycarbonyl)-
d
2,2-dimethyl-1,3-oxazolidin-4-yl]aziridine-1,2-dicarboxylate 13
38.4, 56.8, 64.1, 68.3, 76.0, 82.2, 98.3, 113.1, 155.9, 202.3. HRMS (ES
Q-TOF) calcd for C16H24N2NaO5 (MþNa)þ: 347.1583; found:
347.1576.
Yellow oil (0.73 g, 59%). [
1698 cmꢁ1 1H NMR (200 MHz, CDCl3)
(d, J 8.8 Hz,1H), 3.49–3.98 (m, 2H), 4.02–4.27 (m, 4H), 4.30–4.42 (m,
1H). 13C NMR (50 MHz, CDCl3)
: 13.8, 14.1, 25.1, 25.9, 28.1, 51.1, 57.0,
a
]
D
þ3.4 (c 1.0, CHCl3). IR: 2254, 1756,
.
d: 0.93–1.72 (m, 21H), 3.31
d
4.3.10. tert-Butyl (4S)-4-[(2R,3R)-3-cyano-3-(2,2-dimethyl
propanoyl)-1-(ethoxycarbonyl)aziridin-2-yl]-2,2-dimethyl-1,3-
oxazolidine-3-carboxylate 17
63.6, 64.4, 65.1, 74.8, 80.6, 94.7, 115.7, 156.5, 158.3, 162.3. HRMS (ES
Q-TOF) calcd for C19H29N3NaO7 (MþNa)þ: 434.1903; found:
434.1917.
Pale yellow oil (1.05 g, 83%). [
2222, 1744, 1697 cmꢁ1 1H NMR (300 MHz, CDCl3)
(m, 27H), 3.05 (d, J 8.7 Hz, 1H), 3.86–4.32 (m, 5H). 13C NMR
(75 MHz, CDCl3) : 14.0, 25.5 (2C), 28.2, 28.6, 39.3, 53.7, 63.4,
a
]
þ16.4 (c 1.0, CHCl3). IR:
D
.
d: 0.99–1.85
4.3.4. Diethyl (2S,3S)-2-cyano-3-[(4S)-3-(tert-butoxycarbonyl)-
2,2-dimethyl-1,3-oxazolidin-4-yl]aziridine-1,2-dicarboxylate 130
d
Pale yellow oil (0.20 g, 16%). [
1756, 1698 cmꢁ1. 1H NMR (200 MHz, CDCl3)
3.27 (d, J 5.5 Hz, 1H), 3.78–4.05 (m, 2H), 4.10–4.36 (m, 4H), 4.40–
4.56 (m, 1H). 13C NMR (50 MHz, CDCl3)
: 13.6, 14.8, 25.6 (2C), 28.1,
a
]
þ2.2 (c 1.0, CHCl3). IR: 2254,
68.5, 73.6, 78.9, 80.2, 94.3, 116.0, 157.2, 158.3, 201.7. HRMS (ES
Q-TOF) calcd for C21H33N3NaO6 (MþNa)þ: 446.2267; found:
446.2272.
D
d
: 0.95–1.72 (m, 21H),
d
51.3, 57.5, 62.8, 64.8, 67.8, 73.5, 81.8, 95.1, 113.2, 155.8, 157.1, 161.6.
HRMS (ES Q-TOF) calcd for C19H29N3NaO7 (MþNa)þ: 434.1903;
found: 434.1920.
4.4. Synthesis of diethyl (2R,3S)-2-cyano-3-[(1R)-1,2-
dihydroxyethyl]aziridine-1,2-dicarboxylate (19)
To a solution of 12 (0.2 mmol) in THF (2.0 mL) was added
2 M hydrochloric acid (4 mL). The reaction mixture was stirred
for 30 min at room temperature. The reaction was quenched
with saturated aqueous NaHCO3, the mixture was extracted
with ethyl acetate, the organic layer washed with brine, dried
over Na2SO4, and the solvents evaporated under reduced
pressure. Purification by short plugs filled with silica gel (ethyl
4.3.5. Ethyl (2R,3S)-2-cyano-3-[(4S)-2,2-dimethyl-1,3-dioxolan-4-
yl]-2-(phenylcarbonyl)aziridine-1-carboxylate 14
Pale yellow oil (0.74 g, 72%). [
1740, 1697 cmꢁ1 1H NMR (200 MHz, CDCl3)
3.23 (d, J 8.5 Hz, 1H), 3.96–4.34 (m, 5H), 7.50–7.94 (m, 5H). 13C
NMR (50 MHz, CDCl3) : 13.8, 24.8, 25.3, 53.1, 57.0, 63.7, 67.9, 74.5,
a
]
D
þ15.1 (c 1.0, CHCl3). IR: 2203,
.
d: 1.01–1.76 (m, 9H),
d
94.2, 115.0, 127.6, 128.6, 129.3, 134.2, 157.3, 199.0. HRMS (ES Q-
TOF) calcd for C18H20N2NaO5 (MþNa)þ: 367.1270; found:
367.1258.
acetate/methanol 95:5, 100 mL) gave 19 as
(0.05 g, 87%). [
þ3.0 (c 1.0, CHCl3). IR: 3585, 3391, 2256,
1748 cmꢁ1 1H NMR (200 MHz, CDCl3)
3.36 (d, J 8.1 Hz, 1H), 3.74–4.00 (m, 2H), 4.12–4.26 (m, 4H),
4.30–4.47 (m, 1H), 6.69 (br, 2H). 13C NMR (50 MHz, CDCl3)
13.8, 14.1, 36.6, 50.2, 63.9, 64.1, 64.5, 69.7, 112.8, 157.6, 162.1.
HRMS (ES Q-TOF) calcd for C11H17N2O6 (MþH)þ: 273.1087;
found: 273.1095.
a white wax
a
]
D
.
d: 1.12–1.38 (m, 6H),
4.3.6. Ethyl (2S,3R)-2-cyano-3-[(4S)-2,2-dimethyl-1,3-dioxolan-4-
yl]-2-(phenylcarbonyl)aziridine-1-carboxylate 140
d:
Pale yellow oil (0.19 g, 18%). [
a]
þ11.1 (c 1.0, CHCl3). IR: 2203,
D
1740, 1697 cmꢁ1 1H NMR (200 MHz, CDCl3)
.
d: 0.98–1.74 (m, 9H),

488
S. Fioravanti et al. / Tetrahedron 65 (2009) 484–488
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4.5. Synthesis of diethyl (2R,3R)-3-[(1R)-1-amino-2-
hydroxyethyl]-2-cyanoaziridine-1,2-dicarboxylate (20)
3. Fioravanti, S.; Marchetti, F.; Pellacani, L.; Ranieri, L.; Tardella, P. A. Tetrahedron:
Asymmetry 2008, 19, 231–236.
4. Mulzer, J. In Organic Synthesis Highlights; Mulzer, J., Altenbach, H.-J., Braun, M.,
Krohn, K., Reissig, H.-U., Eds.; VCH Verlagsgesellschaft: Weinheim, 1991;
pp 243–250.
Starting from 13, the above procedure was followed, heating the
mixture at 65 ꢂC for 1.5 h. After working, the crude mixture was
purified by flash chromatography (ethyl acetate/methanol 95:5)
giving a viscous oil (0.029 g, 51%). [
3372, 2253, 1757, 1697 cmꢁ1. 1H NMR (200 MHz, CDCl3)
(m, 6H), 2.80 (br, 2H), 3.26 (d, J 8.1 Hz, 1H), 3.50–3.95 (m, 2H), 4.18–
4.29 (m, 5H), 6.52 (br, 1H). 13C NMR (50 MHz, CDCl3)
: 13.6, 14.3,
a]
D þ9.2 (c 1.0, CHCl3). IR: 3593,
5. Liang, X.; Andersch, J.; Bols, M. J. Chem. Soc., Perkin Trans. 1 2001, 2136–
2157.
d
: 1.25–1.34
6. Texier-Boullet, F.; Foucaud, A. Tetrahedron Lett. 1982, 23, 4927–4928.
7. The E isomerism is due to the minimal steric hindrance of the cyano group. (a)
Wang, S. X.; Li, J. T.; Yang, W. Z.; Yin, Y. H.; Xie, Z. H. Synth. Commun. 2004, 34,
829–834; (b) Al-Shihry, S. S. Molecules 2004, 9, 658–665; (c) Shi, D.-q.; Wang,
X.-s.; Yao, C.-s.; Mu, L. J. Chem. Res., Synop. 2002, 344–345; (d) Kvaran, A.; As-
geirsson, B. I.; Geirsson, J. K. F. J. Mol. Struct. 2001, 563–564; (e) Shanthan Rao,
P.; Venkataratnam, R. V. Tetrahedron Lett. 1991, 32, 5821–5822; (f) Nicolaou, K.
C.; van Delft, F.; Ohshima, T.; Vourloumis, D.; Xu, J.; Hosokawa, S.; Pfefferkorn, J.;
Kim, S.; Li, T. Angew. Chem., Int. Ed. 1997, 36, 2520–2524; (g) Andersen, N. H.;
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8. Fioravanti, S.; Morreale, A.; Pellacani, L.; Tardella, P. A. Synlett 2004, 1083–1085.
9. Burini, E.; Fioravanti, S.; Morreale, A.; Pellacani, L.; Tardella, P. A. Synlett 2005,
2673–2675.
10. (a) Fioravanti, S.; Loreto, M. A.; Pellacani, L.; Tardella, P. A. Tetrahedron Lett. 1993,
34, 4353–4354; (b) Mash, E. A.; Hemperly, S. B.; Nelson, K. A.; Hedidt, P. C.; Van
Deusen, S. J. Org. Chem. 1990, 55, 2045–2055; (c) Mash, E. A.; Hemperly, S. B.
J. Org. Chem. 1990, 55, 2055–2060.
d
35.6, 50.0, 53.9, 59.8, 61.8, 62.9, 115.5, 157.8, 166.7. HRMS (ES Q-TOF)
calcd for C11H18N3O5 (MþH)þ: 272.1246; found: 272.1252.
Acknowledgements
This research was carried out within the framework of the Na-
tional Project ‘Stereoselezione in Sintesi Organica. Metodologie ed
Applicazioni’, supported by the Italian Ministero dell’Istruzione
`
`
dell’Universita e della Ricerca (MIUR) and by the Universita degli
Studi di Roma ‘La Sapienza’.
References and notes
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